Program Director/Principal Investigator (Last, First, Middle): Teich, Andrew, Franklin Project Summary The goal of this proposal is to identify FDA approved compounds that will rescue synaptic dysfunction in Alzheimer?s Disease (AD). This goal is motivated by the observation that one of the earliest events in AD is synaptic dysfunction. In microscopic post-mortem studies, synaptic loss correlates strongly with pre-mortem cognitive status, and serves as a better predictor of pre-mortem cognitive status than either plaque or tangle pathology. Faced with this evidence, multiple groups have proposed that synaptic dysfunction is central to the pathophysiology of AD. Our laboratory has previously utilized novel datamining techniques on RNA expression data to identify master regulators of synaptic and neurophysiologic dysfunction in AD. This computational effort has identified transcriptional regulators whose dysfunction in AD is predicted to cause impairment in expression of synaptic genes (we refer to these transcriptional regulators as ?synaptic master regulators,? or synaptic MRs). Using similar techniques, we propose to screen a library of FDA-approved compounds for their ability to support synaptic function in AD by appropriately modifying disease-relevant synaptic MRs. At the end of this project, we will have a list of FDA-approved compounds that rescue synaptic MR dysfunction. Although this is the primary endpoint of this project, we will also generate the following secondary deliverables; 1) A rat neuronal interactome, which predicts a regulon for every transcriptional regulator in rat neurons, 2) A human iPSC neuronal interactome, which predicts a regulon for every transcriptional regulator in human iPSC neurons, and 3) A list of all transcriptional regulators affected by a library of FDA-approved compounds. These additional deliverables will be usable for drug discovery of other neurologic diseases. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page